A major risk factor for the development of asthma is the presence of allergies and elevated serum IgE levels. Normally IgE production by B cells is tightly regulated by a complex network of positive and negative stimuli. The same stimuli that drive IgE synthesis, CD40 and IL-4, simultaneously induce the expression of CD23, the low-affinity IgE receptor. Binding of IgE to CD23 then mediates a negative feedback loop that is critical for limiting IgE responses. Two alternatively spliced forms of CD23 (CD23a and CD23b) exist in man. CD23a and CD23b only differ by the presence of an inhibitory signaling motif (ITIM) found in CD23a but not in CD23b, suggesting that CD23a and CD23b differ in their ability to mediate inhibitory signals. Abnormalities in the IgE regulatory network have been demonstrated in human allergic disorders. When compared to B cells from non-atopic individuals, B cells from atopic subjects are hyperresponsive to CD40 and/or IL-4. This results in the overproduction of IgE as well as in the induction of abnormally high levels of CD23. The mechanisms by which the "superinduction" of CD23 expression observed in atopic individuals fails to mediate an effective inhibitory feedback loop are not fully understood. Our laboratory utilizes the induction of CD23 as a model system to understand the molecular mechanisms responsible for the deregulation of the IgE network exhibited by allergic patients. Our initial studies have focused on the control of the ITIM-less CD23b isoform. We have shown that expression of CD23b is controlled by a multiprotein complex, containing Stat6, IRF-4, and BCL-6. The major goal of this proposal is to explore the hypothesis that allergic individuals display defects in the molecular mechanisms controlling CD23 expression and that induction of CD23 in these patients is skewed toward the ITIM-less CD23b isoform. Specifically we will: (1) further define the molecular mechanisms regulating the ITIM-containing CD23a isoform, (2) determine whether the expression/induction of the two CD23 isoforms differ in allergic vs. healthy individuals, and (3) assess whether known variants of components of the CD23 signaling cascade (HIL-4Ra, Stat6, and BCL-6) are associated with CD23 "superinduction" and/or CD23b skewing. Completion of these studies will yield a better understanding of the molecular mechanisms responsible for the dysregulation of the IgE network found in allergic patients. Furthermore, knowledge of these mechanisms may provide novel targets for therapeutic intervention in asthma.